In Vitro Modelling of Respiratory Virus Infections in Human Airway Epithelial Cells – A Systematic Review

Abstract

Respiratory tract infections (RTI) are a major cause of morbidity and mortality in humans. A large number of RTIs is caused by viruses, often resulting in more severe disease in infants, elderly and the immunocompromised. Upon viral infection, most individuals experience common cold-like symptoms associated with an upper RTI. However, in some cases a severe and sometimes life-threatening lower RTI may develop. Reproducible and scalable in vitro culture models that accurately reflect the human respiratory tract are needed to study interactions between respiratory viruses and the host, and to test novel therapeutic interventions. Multiple in vitro respiratory cell culture systems have been described, but the majority of these are based on immortalized cell lines. Although useful for studying certain aspects of viral infections, such monomorphic, unicellular systems fall short in creating an understanding of the processes that occur at an integrated tissue level. Novel in vitro models involving primary human airway epithelial cells and, more recently, human airway organoids, are now in use. In this review, we describe the evolution of in vitro cell culture systems and their characteristics in the context of viral RTIs, starting from advances after immortalized cell cultures to more recently developed organoid systems. Furthermore, we describe how these models are used in studying virus-host interactions, e.g. tropism and receptor studies as well as interactions with the innate immune system. Finally, we provide an outlook for future developments in this field, including co-factors that mimic the microenvironment in the respiratory tract.

Experimental Models of COVID-19

“…In vitro cell lines have been used in several studies to aid in the understanding of pathogenesis, tropism and treatment of respiratory virus infections ( Rijsbergen et al., 2021 ). Immortalized cell lines are able to help researchers discover the different cells needed for the infections seen in in-vivo models and are able to be manipulated.…”

Three-Dimensional Cell Culture Models to Study Respiratory Virus Infections Including COVID-19

“…This proves that generation of human lung 3D cultures using Matrigel can mimic the lung function in vivo and thus be used be a useful model to study viral infections including SARS-CoV-2 [ 23 ].…”

“…As such, Dr. Shuibing Chen and collaborators have generated human pluripotent stem cell-derived lung and colonic organoids (hPSC-LOs and hPSC-COs) using 3D cultures to better understand the disease mechanism of COVID-19 and identify candidate dugs that can block SARS-CoV-2 entry [ 23 ]. In their recent publication in Nature, they have shown that lung organoids were permissive to SARS-CoV-2 as expected as the virus primarily targets the respiratory tract, accompanied by robust production in chemokines, which is very similar to what is seen in vivo [ 23 ]. As patients with COVID-19 may also experience gastrointestinal symptoms, the response of colonic organoids (hPSC-COs) to SARS-CoV-2 infection was also explored.…”

“…As patients with COVID-19 may also experience gastrointestinal symptoms, the response of colonic organoids (hPSC-COs) to SARS-CoV-2 infection was also explored. It was demonstrated that several colonic cell types in hPSC-COs, especially enterocytes, expressed ACE2 (the receptor for SARS-CoV-2), thus are permissive to the virus [ 23 ]. The human 3D models were then used to screen for a library FDA-approved drugs.…”

“…The human 3D models were then used to screen for a library FDA-approved drugs. Several drugs, including Imatinib, mycophenolic acid, and quinacrine dihydrochloride were shown to inhibit SARS-CoV-2 entry into both lung and colonic organoids [ 23 ].…”